The proposed NIH K99/R00 application is to assist the candidate, Dr. Canhua Xiao, to become an independent investigator with the research focusing on understanding the biological mechanism of fatigue in patients with head and neck cancer (HNC) receiving radiotherapy (RT). Fatigue, as one of the most common and distressing symptoms in patients with cancer, has a significant influence on patients' quality of life, surviva, and health care utilization. Patients with HNC, typically receiving RT, have particularly high rate of fatigue during RT, and this fatigue is still significant at one year post RT. Our previous study of HNC patients showed that RT-induced fatigue was significantly related to multiple treatment-related symptoms (i.e. mucositis and dry mouth). Understanding the biological mechanisms of fatigue may be the key to its successful management, and benefit other related symptoms as well. Recent research has shown a potential linkage between fatigue and inflammation that may provide novel insights into the biological mechanism of cancer-related fatigue. The proposed study will further clarify and broaden the understanding of this association from a unique pro- and anti- inflammatory signaling perspective; both molecular and genetic mechanisms will be investigated. A longitudinal descriptive design will be employed to observe this association in patients with HNC from before RT to one-year post-RT. During the K99 phase, the candidate will seek to establish the relationship between fatigue and pro-inflammation nuclear factor (NF)-?B signaling pathway in the acute symptom phase (from pre- to three months post-RT). After the candidate has gained more knowledge and skills in neuroendocrine, immunology, and genetics during the K phase, the R00 phase will examine the mechanism of persistent fatigue with additional anti-inflammatory signaling involving glucocorticoid and gene expression analyses until one-year post RT. Novel findings from this study will provide insights into the biological mechanism of fatigue in patients with HNC receiving RT. This may further help to elucidate the biological mechanism of a HNC specific symptom cluster. New pharmacologic targets for the management of fatigue may be revealed from data analysis. To accomplish these goals, a strong mentor team with internationally or nationally recognized experts has been build, including expertise in biobehavioral science and fatigue (Dr. Andrew Miller), cancer symptom assessment and management (Dr. Deborah W. Bruner), and bioinformatics and biostatistics (Dr. Jeanne Kowalski). This team also includes three specialists on radiation oncology and head and neck cancer (Dr. Jonathan J. Beitler), immune and neuroendocrine laboratory techniques (Dr. Thaddeus Pace), and molecular genetics (Dr. Alicia Smith). Since a spectrum of new knowledge and skills regarding biobehavioral research and genetics are required for candidate's career as an independent scientist, this K99/R00 award will be extremely important and necessary to achieve the candidate's career objectives and expand the science of symptom assessment and therapeutics.